Introduction
The side-effects and long-term sequelae of anti-cancer chemotherapy remain a major
source of concern for both patients and clinicians despite the improved efficacy and
enhanced survival offered by modern treatments. Current drugs or other approaches
to counteract chemotherapy-induced adverse effects are often incompletely effective,
frequently do not address potential longer-term sequelae or may even induce other
side-effects which only add to patient discomfort. New approaches to improve tolerance
and reduce sequelae of cancer chemotherapy are urgently needed and the present Research
Topic focuses on this issue and highlights several areas of progress.
Nausea and vomiting are amongst the most feared side-effects for patients embarking
on cancer chemotherapy. Though current treatments to control acute chemotherapy-induced
nausea and vomiting (CINV) are reasonably effective in most patients, delayed CINV
is more difficult to manage. The review by Rapoport describes the pathogenesis, incidence
and current treatment of delayed CINV, and highlights that this symptom is frequently
underestimated and often poorly controlled, even when acute CINV is adequately managed.
The release of substance P and its effect on neurokinin-1 (NK-1) receptors is a key
step in the development of delayed CINV. Rudd et al. describe pre-clinical studies
in animal models (ferrets, house musk shrews) of one NK-1 antagonist, netupitant,
as a broad antiemetic (i.e., not only for CINV). In fact, these studies paved the
way for the incorporation of this particular drug to the clinic. One of the drawbacks
of rodent models in the development of antiemetic drugs is that rodents lack the emetic
reflex. However, indirect markers may be used (Andrews and Sanger, 2014) and Yamamoto
et al. describe a new potential indirect marker of nausea-like behavior based on monitoring
facial expression in the rat. These authors showed the ratio between longitudinal
and axial eye dimensions (eye-opening index) decreased after cisplatin administration
and this effect was inhibited by conventional antiemetics.
Other gastrointestinal side-effects of cancer chemotherapy are also common and can
be both distressing and potentially fatal for patients. In their review, Cinausero
et al. describe the pathobiology and treatment of cancer treatment-related mucosal
injury. Both oral and gastrointestinal mucositis may cause local ulceration and pain,
which in turn may lead to anorexia, malabsorption, weight loss, anemia, fatigue and
increased risk of sepsis. It is important to note that despite much prior research
on oral mucositis, safe and effective preventive measures and treatments are still
lacking. This likely reflects the complexity of the pathobiology of gastrointestinal
mucositis, and highlights the fact that mucosal injury probably contributes to other
chemotherapy-induced gastrointestinal disorders. McQuade et al. describe the pathophysiology,
and current and emerging treatments for chemotherapy-induced constipation (CIC) and
diarrhea (CID), both of which are common and may require dose reductions, delays or
even cessation of treatment. CID is potentially fatal due to dehydration and electrolyte
imbalance and current therapeutic approaches include re-hydration, loperamide, and
octreotide. However, pre-clinical and clinical studies, of new treatments for CID
are described. These include inhibitors of calcium-activated chloride channels, β-glucuronidase
inhibitors, antibiotics, probiotics, and cannabinoid agonists. The authors also emphasize
that CIC is more frequent and severe than commonly recognized. Over-use of anti-diarrhoeal
treatments for CID is one frequent cause of CIC, but other mechanisms of CIC are not
well understood. Current treatments often include laxatives and certain prokinetic
agents. However, agonists targeting intestinal guanylate cyclase C or chloride channels
show promise as potential targets for future studies for CIC. Interestingly, using
radiographic methods in rats, Vera et al. showed that a CB1 receptor cannabinoid antagonist
prevented the effect of acute vincristine on gastrointestinal motility, particularly
in the small intestine. Thus, inactivation of the cannabinoid system might be useful
to counteract CIC, whilst cannabinoid receptor activation might be used to counteract
CID (Abalo et al., 2017; McQuade et al.).
With the expanded use of anti-cancer treatments in different groups of patients, the
profile of toxicities associated with well-established agents, such as platinum-based
chemotherapies, continues to broaden. One example, namely the occurrence of hypersensitivity
reactions to carboplatin in children being treated for solid tumors such as low-grade
glioma, is reviewed by Ruggiero et al. Studies show that such hypersensitivity reactions
occur in up to 47% of children treated with this agent. Younger children, girls and
those with other allergies are at higher risk and the incidence rises with increased
number of infusions rather than simply drug dosage. Another platinum-based chemotherapeutic,
cisplatin, may increase the risk of cardiovascular disease in cancer survivors. Herradón
et al. explored the possible mechanisms for this, using 5 weekly intraperitoneal injections
of cisplatin, in male Wistar rats. In their model, there was evidence of vascular
endothelial changes at lower doses and impacts on cardiac function at the highest
dose. In contrast to cardiovascular toxicity, cisplatin-induced nephrotoxicity is
well recognized and Malik et al. report encouraging results for a potential protective
effect of a botanical, Emblica officinalis (Indian gooseberry). Premedication with
E. officinalis protected male Wistar rats from nephrotoxicity with reduction in the
inflammation and oxidative damage induced by a single intraperitoneal injection of
cisplatin. Evidence of chronic subclinical skeletal muscle toxicity from chemotherapy
is accumulating and this has important implications for longer-term health status
for large numbers of cancer survivors. Unfortunately, there is still a lack of detailed
mechanistic studies investigating the potential impact of anti-cancer agents on skeletal
muscle but the manuscript by Sorensen et al. is the first to describe the direct effects
of repeated oxaliplatin dosing on skeletal muscle, including aspects of skeletal muscle
mitochondrial function. In addition, they show that the small molecule, BGP-15, protects
against oxaliplatin-induced muscle wasting, muscle collagen deposition and changes
in muscle mitochondrial function in their model which uses male BALB/c mice receiving
six intraperitoneal injections over 12 days.
Central and peripheral neurotoxicity caused by anti-cancer drugs can last many years
after the end of treatment and can dramatically reduce functional capacity and quality
of life in cancer survivors. A review of clinical studies on biological markers associated
with cognitive impairments in cancer patients during and after chemotherapy by Castel
et al. is included in this Research Topic. In it the authors identified studies showing
changes in a number of circulating factors and cerebrospinal fluid constituents which
were associated with chemotherapy-induced persistent cognitive dysfunctions. These
factors along with genetic polymorphisms might be used as predictive markers to identify
patients predisposed to cognitive deficits caused by chemotherapy.
Chemotherapy-induced peripheral neuropathy (CIPN) is caused by many anti-cancer drugs
including platinum-based agents, vinca alkaloids, taxanes, and proteasome and angiogenesis
inhibitors. Long-term CIPN is associated with high morbidity including depression,
ataxia, insomnia. Kerckhove et al. provide a comprehensive review of pathophysiological
mechanisms, symptoms and risk factors of long-term CIPN induced by specific types
of chemotherapeutic drugs. However, prevention and treatment strategies for long-term
CIPN are not well-developed and are urgently needed. Thus, it is gratifying to include
two original studies on this issue, in this Research Topic. Sundar et al. present
a pilot clinical trial assessing limb hypothermia to prevent CIPN induced by paclitaxel
in breast cancer patients. Using nerve conduction recording, the activities of several
sensory and motor nerves were evaluated before, during and after chemotherapy. The
results of this study suggest that continuous-flow limb hypothermia can preserve specific
parameters of nerve conduction and significantly benefit some patients undergoing
paclitaxel chemotherapy. These results are supported by another pilot study providing
evidence that limb hypothermia has a potential to alleviate paclitaxel-induced symptoms
of peripheral neuropathy in breast cancer patients (Younus et al., 2016). Kim et al.
demonstrated that systemic administration of a reactive oxygen species scavenger,
tempol, which has previously been shown to be of benefit in a rat model of cancer-induced
bone pain (Zhou et al., 2018), also ameliorated and prevented neuropathic pain induced
by paclitaxel in rats. As mentioned by McQuade et al. there is evidence that chemotherapy-induced
enteric neuropathy may contribute to the occurrence of permanent gastrointestinal
dysfunction in cancer survivors. Thus, further studies of neuroprotective agents to
combat this type of neurotoxicity may also be warranted.
One of the most startling and exciting changes in cancer treatment over recent years
has been the emergence of therapies aimed at enhancing the patient's own immune response
to their tumor. The immune checkpoint inhibitors are now well-established in the treatment
of malignant melanoma and rapidly expanding their role in the treatment of many other
tumors. However, whilst these agents do not induce severe acute nausea, vomiting or
marrow suppression associated with many traditional cytotoxic agents, it is becoming
clearer that they can lead to a whole range of other immune–related side-effects in
many different organs. Such side-effects are sometimes challenging to identify but
can be life-threatening. Kumar et al.; Kumar et al. provide a detailed and timely
review of current knowledge about these immune-related adverse events and a framework
for clinical management. Other therapeutic approaches, using cell-based therapies
to enhance host immune response to tumors, are also being actively pursued. Mosińska
et al. describe the potential for a combination of host dendritic cells and cytokine-induced
killer cells that are primed to target and kill cells expressing tumor antigens. As
the authors explain, the specificity offered by killing only cells expressing tumor
antigens is potentially a very powerful way to avoid side-effects from other less
targeted cytotoxic treatments. However, for now it is too early to say whether the
promising results from early trials will be fulfilled.
Finally, the combination of natural bioactive compounds with traditional chemotherapeutic
drugs can potentiate anti-cancer efficacy and reduce side-effects of chemotherapy.
In some cases, addition of bioactive compounds may overcome the chemo- or radio-resistance
of cancer cells. These synergistic effects of nutraceutical compounds such as flavonoids,
stilbenes, terpenes, curcumin, and others have been discussed in a review article
by Redondo-Blanco et al. presented in this Research Topic. The authors reviewed current
knowledge on mechanisms of action of these compounds based on studies in colorectal
cancer cells, animal models and clinical trials. However, the use of non-approved
combinations of drugs and unproven remedies may lead to severe side-effects and life-threatening
toxicities. Uhl et al. present a case report on fatal toxicity induced by a combination
of dichloroacetate and artemisinin derivative, artesunate. Both drugs exert anti-cancer
activity in vitro and in vivo, and were trialed in a small number of cancer patients;
however, a combination of these drugs provoked severe liver and bone marrow toxicity
in the patient. The authors discuss the literature on the side-effects of these drugs.
In conclusion, the present Research Topic has already generated a lot of interest
with high numbers of views and citations, but there are still many aspects of this
topic area that deserve further attention. These include the impact of cancer chemotherapy
on sensory functioning such as hearing, approaches to maintain fertility during and
after treatment and the broad long-term impact of systemic anti-cancer treatment on
health and aging in cancer survivors (Cupit-Link et al., 2017). We look forward to
more new studies to answer these and many other related questions and we anticipate
that this will continue to be a dynamic and expanding area of research. Finally, we
hope that by identifying and minimizing or preventing both short and longer-term toxicity
from cancer chemotherapy, the treatments themselves will be better tolerated and more
effective, and the health and wellness of cancer survivors will be enhanced.
Author contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.